In this proposal, we will develop a rapid magnetic resonance spectroscopic imaging (MRSI) sequence that will allow for the optimal acquisition of GABA, glutamate (Glu) and glutamine (Gln) spectra in a clinically reasonable scan-time (less than 1 hour). Our proposed method will combine the current, state-of-the-art magnetic resonance spectroscopy (MRS) techniques for the in vivo measurement of the primary inhibitory neurotransmitter GABA, as well as the primary excitatory neurotransmitter, Glu and Gln with the rapid and established method of proton echo-planar spectroscopic imaging (PEPSI). This novel technique will interleave the specialized MEGAPRESS GABA acquisition with the J-resolved Glu/Gln acquisition to yield an actual metabolic image of these metabolites across the brain in under an hour. The advantage of interleaving these two methods is for the simultaneous acquisition of GABA, Glu and Gln over the same time-course, a vital aspect which is necessary for tracking the activity of this neurotransmitter system after an acute drug challenge. We will first undertake a series of phantom experiments to assess the performance of our sequence in vitro and to validate our method, evaluating the ability of our technique to accurately and precisely track varying concentrations of GABA, Glu and Gln over repeated measures. We will then assess the performance of our novel technique in vivo in a sample of healthy volunteers to assess accuracy and precision in our metabolite measurements in living brains. In our final experiment, we will undertake a drug challenge in healthy volunteers to evaluate the clinical utility of our method in detecting and quantifying drug-induced changes in these neurotransmitters across the brain. Upon completion of this project, we will have developed an important tool for the imaging of GABA, Glu and Gln in vivo. From a public health standpoint, this tool would allow us to further understand the workings of this neurotransmitter system in the human brain by allowing us to map out the various levels of these compounds in brain circuits. This would have important implications in the field of psychiatric research and addiction to understand the neurochemical aberrations that exist in addictive disorders. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop a magnetic resonance spectroscopy protocol on our 4 Tesla whole-body research scanner that combines the superior GABA-editing properties of difference-editing with the rapid multi- voxel coverage of echo-planar spectroscopic imaging. This technology will allow for the rapid yet accurate determination of global GABA distributions in the human brain which could potentially serve as a tool for pharmacology studies investigating the distribution and uptake/washout of GABAergic drugs over several time points.